title: Hepatic loss of miR-122 predisposes mice to hepatobiliary cyst and hepatocellular carcinoma upon diethylnitrosamine exposure.
abstract: Loss of miR-122 causes chronic steatohepatitis and spontaneous hepatocellular carcinoma. However, the consequence of miR-122 deficiency on genotoxic stress-induced liver pathogenesis is poorly understood. Here, we investigated the impact of miR-122 depletion on liver pathobiology by treating liver-specific miR-122 knockout (LKO) mice with the hepatocarcinogen diethylnitrosamine (DEN). At 25 weeks post-DEN injection, all LKO mice developed CK-19-positive hepatobiliary cysts, which correlated with DEN-induced transcriptional activation of Cdc25a mediated through E2f1. Additionally, LKO livers were more fibrotic and vascular, and developed larger microscopic tumors, possibly due to elevation of the Axl oncogene, a receptor tyrosine kinase as a novel target of miR-122, and several protumorigenic miR-122 targets. At 35 weeks following DEN exposure, LKO mice exhibited a higher incidence of macroscopic liver tumors (71%) and cysts (86%) compared to a 21.4% and 0% incidence of tumors and cysts, respectively, in control mice. The tumors in LKO mice were bigger (ninefold, P = 0.015) and predominantly hepatocellular carcinoma, whereas control mice mostly developed hepatocellular adenoma. DEN treatment also reduced survival of LKO mice compared to control mice (P = 0.03). Interestingly, induction of oxidative stress and proinflammatory cytokines in LKO liver shortly after DEN exposure indicates predisposition of a pro-tumorigenic microenvironment. Collectively, miR-122 depletion facilitates cystogenesis and hepatocarcinogenesis in mice on DEN challenge by up-regulating several genes involved in proliferation, growth factor signaling, neovascularization, and metastasis.
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio; Department of Molecular, Cellular and Developmental Biology Program, The Ohio State University, Columbus, Ohio.
authors.forename: Shu-Hao
authors.initials: SH
authors.lastname: Hsu
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio; Department of Molecular, Cellular and Developmental Biology Program, The Ohio State University, Columbus, Ohio.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Huban
authors.initials: H
authors.lastname: Kutay
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; Center for Childhood Cancer, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Hemant
authors.initials: H
authors.lastname: Bid
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Julia
authors.initials: J
authors.lastname: Shreve
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; Center for Biostatistics, The Ohio State University, Columbus, Ohio.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio.
authors.forename: Stefan
authors.initials: S
authors.lastname: Costinean
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Anna
authors.initials: A
authors.lastname: Bratasz
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; Center for Childhood Cancer, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Peter
authors.initials: P
authors.lastname: Houghton
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio; Center for Childhood Cancer, Nationwide Children's Hospital, Columbus, Ohio; Department of Pathology, The Ohio State University, Columbus, Ohio; Experimental Therapeutics Program, College of Medicine, The Ohio State University, Columbus, Ohio. Electronic address: Kalpana.Ghoshal@osumc.edu.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Ghoshal
mesh_terms: D000477:Alkylating Agents / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003560:Cysts / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004052:Diethylnitrosamine / Q000009:adverse effects* / Q000494:pharmacology; D050687:E2F1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020687:cdc25 Phosphatases / Q000096:biosynthesis / Q000235:genetics; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000477:Alkylating Agents; D016207:Cytokines; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D035683:MicroRNAs; C544354:Mirn122 microRNA, mouse; D011518:Proto-Oncogene Proteins; D004052:Diethylnitrosamine; D020794:Receptor Protein-Tyrosine Kinases; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases; D000094963:Axl Receptor Tyrosine Kinase; C000722290:AXL receptor tyrosine kinase, mouse